Glutamate neurotransmitter release depends on a stable precursor cytosolic glutamate concentration. Loss of glutamate by synaptic release will deplete the nerve terminal cytosolic precursor pool unless compensated for by glutamate reuptake and synthesis. Glial uptake efficiently removes released glutamate from the synaptic cleft in order to maintain a low ECF concentration of glutamate. In vivo and in vitro studies indicate that glutamate taken up by glia is converted to glutamine by glutamine synthetase. Glutamine is released from the glia to the ECF where it is taken up by neurons and converted back to glutamate through the action of glutaminase. Despite the critical role of this glutamate/glutamine cycle for normal brain function, little is known about the rate or regulation of this pathway. Recently we have developed and tested in the rat brain a model of this pathway which allows the rate of the glutamate/glutamine cycle to be measured from C MRS measurements of glutamine isotopic labeling. The primary objective of this grant is to determine the rate of the glutamate/glutamine cycle in normal human cortex. C MRS will be used to measured glutamine and glutamate isotopic labeling from infused [1-13C] and [2-13C] glucose. Key aspects of the proposed model of the glutamate/glutamine cycle will be tested through measuring of the effect of altering plasma ammonia concentration on total and anapleurotic glutamine synthesis in subjects with mild hepatic encephalopathy.